. . . . . . "005.003" . . . . "P\u0159edklinick\u00FD profil bezpe\u010Dnosti imatinibu byl stanoven na potkanech, psech, opic\u00EDch a kr\u00E1l\u00EDc\u00EDch. \nP\u0159i studiu toxicity po opakovan\u00E9m pod\u00E1n\u00ED byly pozorov\u00E1ny m\u00EDrn\u00E9 a\u017E st\u0159edn\u011B z\u00E1va\u017En\u00E9 hematologick\u00E9 zm\u011Bny u potkan\u016F, ps\u016F, a opic doprov\u00E1zen\u00E9 zm\u011Bnami v kostn\u00ED d\u0159eni u potkan\u016F a ps\u016F. \nU potkan\u016F a ps\u016F byly c\u00EDlov\u00FDm org\u00E1nem j\u00E1tra. U obou druh\u016F zv\u00ED\u0159at bylo pozorov\u00E1no m\u00EDrn\u00E9 a\u017E st\u0159edn\u00ED zv\u00FD\u0161en\u00ED transamin\u00E1z a m\u00EDrn\u00FD pokles cholesterolu, triglycerid\u016F, celkov\u00FDch protein\u016F a hladiny albuminu. V j\u00E1trech potkan\u016F nebyly nalezeny \u017E\u00E1dn\u00E9 histopatologick\u00E9 zm\u011Bny. Z\u00E1va\u017En\u00E9 toxick\u00E9 zm\u011Bny se zv\u00FD\u0161en\u00EDm jatern\u00EDch enzym\u016F, hepatocelul\u00E1rn\u00ED nekr\u00F3zou, nekr\u00F3zou \u017Elu\u010Dov\u00FDch cest a hyperplazi\u00ED \u017Elu\u010Dovodu byly pozorov\u00E1ny u ps\u016F l\u00E9\u010Den\u00FDch po 2 t\u00FDdny. \nU opic byla po dvou t\u00FDdnech l\u00E9\u010Dby pozorov\u00E1na nefrotoxicita, s lo\u017Eiskovou mineralizac\u00ED a dilatac\u00ED ren\u00E1ln\u00EDch tubul\u016F a tubul\u00E1rn\u00ED nefr\u00F3zou. U n\u011Bkolika zv\u00ED\u0159at bylo pozorov\u00E1no zv\u00FD\u0161en\u00ED urey v krvi (BUN) a kreatininu. U potkan\u016F byla po d\u00E1vk\u00E1ch \u2265 6 mg/kg ve 13t\u00FDdenn\u00ED studii pozorov\u00E1na hyperplazie p\u0159echodov\u00E9ho epitelu ren\u00E1ln\u00ED papily a mo\u010Dov\u00E9ho m\u011Bch\u00FD\u0159e, beze zm\u011Bn parametr\u016F v s\u00E9ru nebo mo\u010Di. P\u0159i chronick\u00E9 l\u00E9\u010Db\u011B imatinibem byl pozorov\u00E1n \u010Detn\u011Bj\u0161\u00ED v\u00FDskyt oportunn\u00EDch infekc\u00ED. \nVe 39t\u00FDdenn\u00ED studii u opic nebyla p\u0159i nejni\u017E\u0161\u00ED d\u00E1vce 15 mg/kg, odpov\u00EDdaj\u00EDc\u00ED p\u0159ibli\u017En\u011B jedn\u00E9 t\u0159etin\u011B maxim\u00E1ln\u00ED hum\u00E1nn\u00ED d\u00E1vky 800 mg stanoven\u00E9 podle t\u011Blesn\u00E9ho povrchu, stanovena hladina bez ne\u017E\u00E1douc\u00EDch \u00FA\u010Dink\u016F -NOAEL (No Observed Adverse Effect Level). U t\u011Bchto zv\u00ED\u0159at do\u0161lo ke zhor\u0161en\u00ED norm\u00E1ln\u011B potla\u010Den\u00E9 mal\u00E1rie. \nVe studi\u00EDch in vitro na bakteri\u00E1ln\u00EDch bu\u0148k\u00E1ch (Ames\u016Fv test), na sav\u010D\u00EDch bu\u0148k\u00E1ch (my\u0161\u00ED lymfomov\u00E9 bu\u0148ky) ani ve studi\u00EDch in vivo u potkan\u016F mikronukle\u00E1rn\u00EDm testem nebyla zji\u0161t\u011Bna genotoxicita imatinibu. Pozitivn\u00ED genotoxick\u00FD \u00FA\u010Dinek imatinibu byl zji\u0161t\u011Bn v testu in vitro na sav\u010D\u00EDch bu\u0148k\u00E1ch (ovari\u00E1ln\u00ED bu\u0148ky k\u0159e\u010Dka \u010D\u00EDnsk\u00E9ho) na klastogenitu (chromozom\u00E1ln\u00ED aberaci) za p\u0159\u00EDtomnosti metabolick\u00E9 aktivace. Dva meziprodukty v\u00FDrobn\u00EDho procesu, kter\u00E9 jsou tak\u00E9 p\u0159\u00EDtomny ve fin\u00E1ln\u00EDm v\u00FDrobku, m\u011Bly pozitivn\u00ED Ames\u016Fv test na mutageniitu. Jeden z t\u011Bchto meziprodukt\u016F byl tak\u00E9 pozitivn\u00ED p\u0159i testov\u00E1n\u00ED na my\u0161\u00EDch lymfomov\u00FDch bu\u0148k\u00E1ch. \nVe studii fertility byla potkan\u00EDm samc\u016Fm po dobu 70 dn\u016F p\u0159ed p\u0159ipu\u0161t\u011Bn\u00EDm pod\u00E1v\u00E1na d\u00E1vka 60 mg/kg, kter\u00E1 p\u0159ibli\u017En\u011B odpov\u00EDd\u00E1 maxim\u00E1ln\u00ED klinick\u00E9 d\u00E1vce 800 mg/den, stanoven\u00E9 podle t\u011Blesn\u00E9ho povrchu. Byl zji\u0161t\u011Bn \u00FAbytek hmotnosti varlat a nadvarlat a sn\u00ED\u017Eeno procento pohybliv\u00FDch spermi\u00ED. Tento \u00FA\u010Dinek nebyl pozorov\u00E1n p\u0159i d\u00E1vce \u2264 20 mg/kg. M\u00EDrn\u00E9 a\u017E st\u0159edn\u00ED sn\u00ED\u017Een\u00ED spermatogeneze bylo tak\u00E9 pozorov\u00E1no u ps\u016F po peror\u00E1ln\u00EDch d\u00E1vk\u00E1ch \u2265 30 mg/kg. Pokud byl imatinib pod\u00E1v\u00E1n samic\u00EDm potkan\u016F 14 dn\u016F p\u0159ed p\u0159ipu\u0161t\u011Bn\u00EDm a a\u017E do 6. dne b\u0159ezosti nebylo ovlivn\u011Bno ani zab\u0159eznut\u00ED ani po\u010Det b\u0159ez\u00EDch samic. Po pod\u00E1v\u00E1n\u00ED d\u00E1vky 60 mg/kg, do\u0161lo u samic potkan\u016F k v\u00FDznamn\u00FDm postimplanta\u010Dn\u00EDm ztr\u00E1t\u00E1m plod\u016F a sn\u00ED\u017Een\u00ED po\u010Dtu \u017Eiv\u00FDch plod\u016F. Tento \u00FA\u010Dinek nebyl pozorov\u00E1n v d\u00E1vk\u00E1ch \u2264 20 mg/kg. \nVe studii pre a postnat\u00E1ln\u00EDho v\u00FDvoje u potkan\u016F po peror\u00E1ln\u00EDm pod\u00E1n\u00ED 45 mg/kg/den byl 14. nebo 15. den zab\u0159eznut\u00ED pozorov\u00E1n rud\u00FD v\u00FDtok z vag\u00EDny. P\u0159i stejn\u00E9 d\u00E1vce stoupnul po\u010Det mrtv\u011B narozen\u00FDch ml\u00E1\u010Fat stejn\u011B jako po\u010Det uhynul\u00FDch po narozen\u00ED mezi 0. a\u017E 4. dnem. U ml\u00E1\u010Fat z vrhu F1, byla p\u0159i stejn\u00E9 d\u00E1vce ni\u017E\u0161\u00ED pr\u016Fm\u011Brn\u00E1 t\u011Blesn\u00E1 hmotnost od narozen\u00ED a\u017E do usmrcen\u00ED a po\u010Det ml\u00E1\u010Fat ve vrhu byl tak\u00E9 sn\u00ED\u017Een. Fertilita F1 nebyla ovlivn\u011Bna po d\u00E1vce 45 mg/kg/den, zat\u00EDmco po\u010Det resorbovan\u00FDch plod\u016F stoupl a klesl po\u010Det \u017Eiv\u011B narozen\u00FDch ml\u00E1\u010Fat. Dle hodnocen\u00ED No Observed Effect Level (NOEL) byla pro mate\u0159sk\u00E1 zv\u00ED\u0159ata a F1 generaci ml\u00E1\u010Fat bezpe\u010Dn\u00E1 d\u00E1vka 15 mg/kg/den (jedna \u010Dtvrtina maxim\u00E1ln\u00ED lidsk\u00E9 d\u00E1vky 800 mg). \nImatinib byl teratogenn\u00ED, pokud byl pod\u00E1v\u00E1n potkan\u016Fm b\u011Bhem organogeneze v d\u00E1vk\u00E1ch \u2265 100 mg/kg, p\u0159ibli\u017En\u011B odpov\u00EDdaj\u00EDc\u00ED maxim\u00E1ln\u00ED klinick\u00E9 d\u00E1vce 800 mg/den, stanoven\u00E9 podle t\u011Blesn\u00E9ho povrchu. Teratogenn\u00ED \u00FA\u010Dinky zahrnovaly exencefalii nebo encefalokelu, absenci nebo redukci front\u00E1ln\u00EDch kost\u00ED a absenci pariet\u00E1ln\u00EDch kost\u00ED. Tyto \u00FA\u010Dinky nebyly pozorov\u00E1ny p\u0159i d\u00E1vk\u00E1ch \u2264 30 mg/kg.\n \nV\u00FDsledky 2let\u00E9 studie kancerogenity u potkan\u016F, kter\u00FDm byl pod\u00E1v\u00E1n imatinib v d\u00E1vce 15, 30 a 60 mg/kg/den uk\u00E1zaly statisticky v\u00FDznamn\u00E9 sn\u00ED\u017Een\u00ED d\u00E9lky \u017Eivota u samc\u016F p\u0159i d\u00E1vce 60 mg/kg/den a u samic p\u0159i d\u00E1vce \u2265 30 mg/kg/den. Histopatologick\u00E1 vy\u0161et\u0159en\u00ED jako hlavn\u00ED p\u0159\u00ED\u010Dinu smrti nebo d\u016Fvodu pro utracen\u00ED zv\u00ED\u0159at odhalily kardiomyopatii (u obou pohlav\u00ED), chronickou progresivn\u00ED nefropatii (u samic) a papilomy p\u0159edko\u017Ekov\u00E9 \u017El\u00E1zky. C\u00EDlov\u00FDmi org\u00E1ny, pokud se t\u00FDk\u00E1 neoplastick\u00FDch zm\u011Bn, byly ledviny, mo\u010Dov\u00FD m\u011Bch\u00FD\u0159, uretra, p\u0159edko\u017Ekov\u00E1 a klitorid\u00E1ln\u00ED \u017El\u00E1zka, tenk\u00E9 st\u0159evo, p\u0159\u00ED\u0161t\u00EDtn\u00E1 t\u011Bl\u00EDska, nadledvinky a nesekretorick\u00E1 \u010D\u00E1st \u017Ealude\u010Dn\u00ED st\u011Bny. \nByly zaznamen\u00E1ny p\u0159\u00EDpady vzniku papilom\u016F/karcinom\u016F p\u0159edko\u017Ekov\u00E9/klitorid\u00E1ln\u00ED \u017El\u00E1zky p\u0159i d\u00E1vce od 30 mg/kg/den a v\u00EDce, co\u017E reprezentuje p\u0159ibli\u017En\u011B 0,5n\u00E1sobek d\u00E1vky 400 mg/den b\u011B\u017En\u011B u\u017E\u00EDvan\u00E9 u \u010Dlov\u011Bka (podle AUC), nebo 0,3n\u00E1sobek d\u00E1vky 800 mg/den u\u017E\u00EDvan\u00E9 u \u010Dlov\u011Bka, a 0,4n\u00E1sobek d\u00E1vky 340 mg/m2/den u d\u011Bt\u00ED (podle AUC). Dle hodnocen\u00ED No Observed Effect Level (NOEL) byla bezpe\u010Dn\u00E1 d\u00E1vka 15 mg/kg/den. Ren\u00E1ln\u00ED adenom/karcinom a papilom mo\u010Dov\u00E9ho m\u011Bch\u00FD\u0159e a uretry, adenokarcinomy tenk\u00E9ho st\u0159eva, adenomy p\u0159\u00ED\u0161t\u00EDtn\u00FDch t\u011Bl\u00EDsek, benign\u00ED a malign\u00ED medul\u00E1rn\u00ED tumory nadledvinek a papilomy/karcinomy nesekretorick\u00E9 \u010D\u00E1sti \u017Ealude\u010Dn\u00ED st\u011Bny byly pozorov\u00E1ny p\u0159i d\u00E1vce 60 mg/kg/den, co\u017E reprezentuje p\u0159ibli\u017En\u011B 1,7n\u00E1sobek d\u00E1vky 400 mg/den b\u011B\u017En\u011B u\u017E\u00EDvan\u00E9 u \u010Dlov\u011Bka (podle AUC) nebo d\u00E1vku 800 mg/den b\u011B\u017En\u011B u\u017E\u00EDvan\u00E9 u \u010Dlov\u011Bka, a 1,2n\u00E1sobek d\u00E1vky 340 mg/m2/den u d\u011Bt\u00ED (podle AUC). Dle hodnocen\u00ED No Observed Effect Level (NOEL) byla bezpe\u010Dn\u00E1 d\u00E1vka 30 mg/kg/den. \nMechanismus a z\u00E1va\u017Enost t\u011Bchto n\u00E1lez\u016F ze studie kancerogenity u potkan\u016F nen\u00ED je\u0161t\u011B u \u010Dlov\u011Bka objasn\u011Bn. \nNon-neoplastick\u00E9 l\u00E9ze neprok\u00E1zan\u00E9 v d\u0159\u00EDv\u011Bj\u0161\u00EDch p\u0159edklinick\u00FDch studi\u00EDch se vyskytovaly v\u00A0kardiovaskul\u00E1rn\u00EDm syst\u00E9mu, pankreatu, endokrinn\u00EDch org\u00E1nech a zubech. Nejd\u016Fle\u017Eit\u011Bj\u0161\u00ED zm\u011Bny zahrnovaly srde\u010Dn\u00ED hypertrofii a dilataci, vedouc\u00ED k p\u0159\u00EDznak\u016Fm srde\u010Dn\u00ED nedostate\u010Dnosti u n\u011Bkter\u00FDch zv\u00ED\u0159at.\n"@cs . . . . . . "5.3\tP\u0159edklinick\u00E9 \u00FAdaje vztahuj\u00EDc\u00ED se k\u00A0bezpe\u010Dnosti"@cs .